More than a third of all medical prescriptions contain the decalin subunit embedded within the core molecular skeleton. The prevalence of biologically-potent decalins has sporned numerous syntheses though a pressing need still exists for rapid, asymmetric decalin syntheses. The proposal addresses this need through new bond forming reactions that exploit the unique reactivity of the nitrile group. The focus of this proposal is to develop rapid syntheses of highly substituted, chiral decalins. Key to this objective is a conceptually new palladium-catalyzed addition that addresses the long-standing difficulty of performing conjugate additions to alkenenitriles. Two complementary asymmetric conjugate addition strategies are proposed for accessing a series of decalin precursors. Engaging these conjugate addition products in an oxidative cyclization cascade can conceptually provide access to a diverse array of nitrile containing decalins, hydrindanes, and octalins. Additionally, the asymmetric conjugate addition products are ideal precursors for a fundamentally new stereoelectronic synthesis of hydrindanes and decalins - core units embedded within steroids and vitamin D metabolites. The generality of this strategy is illustrated in the synthesis of a furanolabdanoid and marasmene, a potential AIDS inhibitor. Synthesizing these targets not only illustrates the rapid construction of potential decalin-containing drugs but illustrates fundamental principles for widespread adoption. The five specific aims of this proposal are to develop: * Asymmetric conjugate additions to alkenenitriles * Oxidative cyclization cascade * New frontiers in stereoelectronic control * Cyclizations of medium-sized carbocycles * The synthesis of marasmene as a potential NNRTI . Fulfilling these aims will advance knowledge of both nitrile-based reactions and NNRTI inhibitors. PUBLIC HEALTH RELEVANCE: Strategies for rapidly assembling biologically-potent decalins are proposed which simultaneously advance the fundamental chemistry of nitriles. Developing this chemistry has profound ramifications for synthesizing nitrile-containing drugs currently on the market and for pharmaceutical syntheses employing nitrile-containing intermediates. The potential of these fundamental advances are illustrated in the synthesis of marasmene, the parent metabolite in a series of structures having exceptional activity as non-nucleoside reverse transcriptase inhibitors of the AIDS virus. [unreadable] [unreadable] [unreadable]